Abstract
BackgroundTendon stem cells (TSCs) have been reported to hold promises for tendon repair and regeneration. However, less is known about the effects of exosomes derived from TSCs. Therefore, we aimed to clarify the healing effects of TSC-derived exosomes (TSC-Exos) on tendon injury.MethodsThe Achilles tendons of Sprague-Dawley male rats were used for primary culture of TSCs and tenocytes, and exosomes were isolated from TSCs. The proliferation of tenocytes induced by TSC-Exos was analyzed using an EdU assay; cell migration was measured by cell scratch and transwell assays. We used western blot to analyze the role of the PI3K/AKT and MAPK/ERK1/2 signaling pathways. In vivo, Achilles tendon injury models were created in Sprague-Dawley rats. Rats (n = 54) were then randomly assigned to three groups: the TSC-Exos group, the GelMA group, and the control group. We used immunofluorescence to detect changes in the expression of inflammatory and apoptotic markers at 1 week after surgery. Histology and changes in expression of extracellular matrix (ECM)-related indices were assessed by hematoxylin-eosin (H&E) staining and immunohistochemistry at 2 and 8 weeks. The collagen fiber diameter of the healing tendon was analyzed at 8 weeks by transmission electron microscopy (TEM).ResultsTSC-Exos were taken up by tenocytes, which promoted the proliferation and migration of cells in a dose-dependent manner; this process may depend on the activation of the PI3K/AKT and MAPK/ERK1/2 signaling pathways. At 1 week after surgery, we found that inflammation and apoptosis were significantly suppressed by TSC-Exos. At 2 and 8 weeks, tendons treated with TSC-Exos showed more continuous and regular arrangement in contrast to disorganized tendons in the GelMA and control groups, and TSC-Exos may help regulate ECM balance and inhibited scar formation. Further, at 8 weeks, the TSC-Exos group had a larger diameter of collagen compared to the control group.ConclusionsOur data suggest that TSC-Exos could promote high-quality healing of injured tendon, which may be a promising therapeutic approach for tendon injury.
Highlights
Tendon injury is a common problem impacting patients’ work and lives and occurs most often during sports and recreational activities [1, 2]
We studied the effect of Tendon stem cells (TSCs)-Exos on tendon matrix-related factors, COL1a1, Collagen type III (COL3a1), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of matrix metalloproteinase (TIMP-1)
We demonstrate that the ratio of type I/III collagen and the proportion of large-diameter fibrils in the experimental group were significantly higher compared to those of the other two groups, indicating that treatment with TSCExos might help to regulate the relative levels of extracellular matrix (ECM) components and strengthen biomechanical properties for tendon injury healing
Summary
Tendon injury is a common problem impacting patients’ work and lives and occurs most often during sports and recreational activities [1, 2]. Tendon healing is a long and complex process comprised of inflammation, proliferation, and remodeling. Because tendon tissue has minimal vascular supply and excessive loading, its ability to self-repair and regenerate after injury is poor [3]. The study of tendon stem cells (TSCs), which are progenitor cells found in the tendon tissue, has received increased attention in recent years. TSCs have the potential of self-renewal and differentiation and have been widely used in tissue engineering and tendon injury healing. Growing studies have shown that the application of TSCs can effectively promote the repair and regeneration of injured tendons [5,6,7,8]. Tendon stem cells (TSCs) have been reported to hold promises for tendon repair and regeneration. We aimed to clarify the healing effects of TSC-derived exosomes (TSC-Exos) on tendon injury
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